Diabetic osteoporosis (DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1 (HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.

糖尿病性骨质疏松症（DOP）是持续威胁糖尿病患者骨骼健康的主要并发症。DOP 的一个关键致病因素是骨细胞活力的丧失。然而，骨细胞死亡的机制仍不清楚。在这里，我们确定了铁下垂，即铁依赖性程序性细胞死亡，是 DOP 小鼠模型中骨细胞死亡的关键机制。糖尿病微环境在体外显着增强骨细胞铁死亡，表现为大量脂质过氧化、铁过载和铁死亡途径的异常激活。RNA测序显示血红素加氧酶1（HO-1）的表达在铁死亡骨细胞中显着上调。进一步的研究结果表明，HO-1 对 DOP 中的骨细胞铁死亡至关重要，并且其启动子活性受上游 NRF2 和 c-JUN 转录因子之间的相互作用控制。靶向铁死亡或 HO-1 通过破坏脂质过氧化和 HO-1 激活之间的恶性循环，有效地挽救了 DOP 中的骨细胞死亡，最终改善了小梁的恶化。我们的研究提供了对 DOP 发病机制的深入了解，我们的结果为临床 DOP 治疗提供了基于机制的策略。